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CA2547137A1 - Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods - Google Patents

Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods Download PDF

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Publication number
CA2547137A1
CA2547137A1 CA002547137A CA2547137A CA2547137A1 CA 2547137 A1 CA2547137 A1 CA 2547137A1 CA 002547137 A CA002547137 A CA 002547137A CA 2547137 A CA2547137 A CA 2547137A CA 2547137 A1 CA2547137 A1 CA 2547137A1
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Prior art keywords
carvedilol
controlled release
microparticle
solvate
release
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CA002547137A
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French (fr)
Inventor
Catherine Castan
Patrick J. Crowley
Florence Guimberteau
Remi Meyrueix
Choon Oh
Gerard Soula
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Flamel Technologies SA
SB Pharmco Puerto Rico Inc
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Individual
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Publication of CA2547137A1 publication Critical patent/CA2547137A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Indole Compounds (AREA)

Abstract

The present invention also relates to carvedilol free base, carvedilol salts, anhydrous forms, or solvates thereof, corresponding pharmaceutical compositions or controlled release formulations, and delivery or dosing methods of carvedilol forms to the lower gastrointestingal tract or methods to treat cardiovascular diseases, which may include, but are not limited to hypertension, congestive heart failure, atherosclerosis, and angina. The present invention relates to controlled release formulations, which comprise various carvedilol forms, which may include, but are not limited to a carvedilol free base or corresponding carvedilol salts, anhydrous forms or solvates thereof.

Claims (73)

1. A controlled release formulation, comprising:

a solubility enhanced carvedilol free base or carvedilol salt, solvate or anhydrous form thereof;

wherein the controlled release formulation following oral dosage exhibits a substantially biphasic plasma profile with a first plasma concentration peak level within within 1-4 hours of ingestion and a second plasma concentration peak level within 5-hours after ingestion.
2. The controlled release formulation according to claim 1, wherein the oral dosage is administered at night.
3. The controlled release formulation according to claim 1, wherein the solubility enhanced carvedilol free base or carvedilol salt, solvate or anhydrous form thereof is an acid addition salt of carvedilol free base.
4. The controlled release formulation according to claim 3, wherein the acid addition salt of carvedilol free base is an acid addition salt formed from a mineral acid or an organic acid.
5. The controlled release formulation according to claim 4, wherein the mineral acid is selected from hydrobromic acid, hydrochloric acid, phosphoric or sulphuric acid, and the organic acid is selected from methansulphuric acid, tartaric acid, maleic acid, acetic acid, citric acid, benzoic acid and the like.
6. The controlled release formulation according to claim 1, wherein the solubility enhanced carvedilol salt, solvate or anhydrous form is selected from the group consisting of carvedilol mandelate, carvedilol lactate, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, carvedilol mesylate, carvedilol phosphate, carvedilol citrate, carvedilol hydrogen bromide, carvedilol oxalate, carvedilol hydrogen chloride, carvedilol hydrogen bromide, carvedilol benzoate, or corresponding solvates thereof.
7. The controlled release formulation according to claim 6, wherein the solubility enhanced carvedilol salt, solvate or anhydrous form thereof is carvedilol phosphate.
8. The controlled release formulation according to claim 1, wherein the formulation is in an oral dosage form.
9. The controlled release formulation according to claim 8, wherein the oral dosage form is a capsule dosage form.
10. The controlled release formulation according to claim 9, wherein the capsule dosage form is comprised of a mixture of two or more populations of coated pellets of different sizes with different associated immediate or controlled release characteristics.
11. A microparticle composition or formulation, which comprises:
a mixture of rapidly releasing and controlled-release microparticles;

wherein the mixture contains carvedilol free base or a carvedilol salt, solvate or anhydrous form thereof;

wherein each rapidly releasing microparticle has a core unit formed by applying a mixture of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof and materials selected from at least one nitrogen containing polymer, a plasticizer or pharmaceutically acceptable excipients onto a cellulose microparticle or pharmaceutically acceptable material; and wherein each core of the rapidly releasing and controlled-release microparticles further are layered or coated with an additional controlled release layer formed from pharmaceutically acceptable excipients.
12. A microparticle composition or formulation of claim 11, wherein the controlled release layer is formed from a mixture of the pharmaceutically acceptable excipients selected from a film former, a plasticiser or other pharmaceutically acceptable excipients.
13. A microparticle composition or formulation, which comprises:

a mixture of:

[a] rapidly-releasing microparticles containing carvedilol free base, or a carvedilol salt, solvate or anhydrous form thereof; and [b] at least two types of controlled-release microparticles containing a carvedilol free base or a carvedilol salt, solvate or anhydrous form thereof;

wherein the rapidly releasing microparticles contain a first dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof different than each of the dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in at least two different types of delayed or controlled-release microparticles;
and wherein rapid release of the first dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the rapidly releasing microparticles is followed by a serial or sequential time-triggered and pH-triggered release of each of the different dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in each of the at least two different types of controlled release microparticles.
14. The microparticle composition or formulation of claim 13, wherein the serial or sequential pH triggered release of each of the different dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in each of the at least two different types of controlled release microparticles occurs at a pH of about 5.5 to a pH of about a pH >
6.4.
15. The microparticle composition or formulation of claim 13, wherein a first maximum plasma drug level following rapid release of the first dosage amount of the carvedilol free base, or the carvedilol salt, solvate, or anhydrous form thereof contained in the rapidly releasing microparticles occur at a time between about 1 hour to about 3 hour following dosage of the microparticle composition or formulation.
16. The microparticle composition or formulation of claim 13, wherein a second maximum plasma drug level following the serial or sequential time-triggered release of each of the different dosage amounts of the carvedilol free base or carvedilol salt, solvate, or anhydrous form thereof contained in each of the at least two different types of controlled release microparticles occur at a time between about 5 hours to about 10 hours following dosage of the microparticle composition or formulation.
17. The microparticle composition or formulation of claim 11, wherein each of the first and second maximum plasma levels following the time and pH
triggered release of each of the different dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the rapidly releasing microparticles and each of the at least two different types of controlled release microparticles results in a controlled release of the total dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the microparticle composition or formulation.
18. The microparticle composition or formulation of claim 17 wherein the first maximum plasma levels following the time and pH triggered release of each of the different dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the rapidly releasing microparticles is about 10% to about 15% of the total dosage amount of carvedilol free base, carvedilol salt, solvate, or anhydrous form thereof contained in the microparticle composition or formulation.
19. The microparticle composition or formulation of claim 18, wherein the first maximum plasma levels following the time and pH triggered release of each of the different dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the rapidly releasing microparticles is about 12.5% of the total dosage amount of carvedilol free base, carvedilol salt, solvate, or anhydrous form thereof contained in the microparticle composition or formulation
20. The microparticle composition or formulation of claim 17, wherein the second maximum plasma levels following the time and pH triggered release of each of the different dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in each of the at least two different types of controlled release microparticles results in a controlled release of between about 85% to about 90% the total dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the microparticle composition or formulation
21. The microparticle composition or formulation of claim 13, wherein a controlled release of the total dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the microparticle composition or formulation occurs in a gastrointestinal tract system.
22. A microparticle formulation for once-a-day therapy, which comprises:

a mixture of:

[a] rapidly releasing microparticles containing carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof; and [b] at least two types of controlled-release microparticles containing carvedilol free base or a carvedilol salt; solvate, or anhydrous form thereof;

wherein the rapidly releasing microparticles contain a first dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof different from each dosage amount contained in each of the at least two different types of delayed or controlled-release microparticles;

wherein the rapidly releasing microparticles exhibit rapid release of the first dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof and the at least two different types of controlled release microparticles exhibit a pH-dependent, a time dependent or a pH-dependent and time-dependent, a triggered serial or sequential sustained prolonged release or controlled release for each of the dosage amounts of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof contained in the at least two different types of controlled release microparticles.
23. A microparticle composition or formulation, which comprises:

[a] a rapidly releasing microparticle type containing carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof;

wherein each rapidly releasing microparticle type is comprised of a rapidly releasing microparticle core unit formed from a mixture of the carvedilol free base or the carvedilol, salt, solvate, or anhydrous form thereof in combination with one or more nitrogen-containing pharmaceutical polymers and a plasticizer or other pharmaceutically acceptable excipients;

[b] at least two different controlled-release microparticle types each containing carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof;

wherein each of the at least two different controlled-release microparticles is comprised of a drug-containing microparticle core unit as defined in [a] above and is further coated with a controlled release layer(s) formed from a film-forming polymer, a plasticizing agent or other pharmaceutically acceptable excipients;

wherein each of the rapidly releasing microparticle type contains the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof dosage amount different from the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof dosage amounts contained in each of the at least two different controlled release microparticle types;

wherein each of the rapidly releasing and at least two different controlled release microparticles are mixed together with materials selected from the group consisting of a surface active, a lubricating agent, an anti-agglomerating agent or other pharmaceutically acceptable excipients.
24. A controlled-release microparticle formulation, which comprises a microparticle ratio mixture formed from:

[1] a first rapidly releasingmicroparticle population, (2] a first controlled release microparticle population; and [3] a second controlled release microparticle population;

wherein each first rapidly releasing microparticle population is formed from a rapid releasing microparticle comprised of a combination of carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof, one or more nitrogen-containing polymers, a plasticizer and, other pharmaceutically acceptable excipients;

wherein each first controlled release microparticle population and each second controlled release microparticle population is comprised of a controlled-release microparticle unit comprised of an active drug loaded core comprised of a combination of a carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof, one or more nitrogen-containing polymers, a plasticizer or pharmaceutically acceptable excipients;

wherein the active drug loaded core of each first controlled release microcapsule and each second controlled release microcapsule is layered with a controlled release layer of film forming polymer(s), or mixtures of film forming polymers thereof, and a plasticizer agent or pharmaceutically acceptable excipients;

wherein each first rapidly releasing microparticle unit, first controlled release microparticle unit and second controlled release microparticle unit each contain a different dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof.
25. The controlled-release microparticle formulation of claim 24, wherein the first rapidly releasing microparticle population contains at least 5%
and no more than 20% of a total dosage of the carvedilol free base or the carvedilol salt, solvate or anhydrous form thereof.
26. The controlled-release microparticle formulation of claim 25, wherein the first rapidly releasing microparticle population contains at least 10% and no more than 15% of the total dosage of the carvedilol free base or the carvedilol salt, solvate or anhydrous form thereof.
27. The controlled-release microparticle formulation of claim 24, wherein the first controlled-release microparticle population contains at least 25% and no more than 50% of a total dosage of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof.
28. The controlled-release microparticle formulation of claim 24, wherein the second controlled-release microparticle population contains at least 40% and no more than 60% of a total dosage of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof.
29. The controlled-release microparticle formulation of claim 24, wherein each first rapidly releasing microparticle unit, first controlled release microparticle unit and second controlled release microparticle unit has a particle size of between 50 µm and 1000 µm.
30. The controlled-release microparticle formulation of claim 24, wherein the microparticle formulation is an oral dosage form.
31. The controlled-release microparticle formulation of claim 30, wherein the oral dosage form is administered at night.
32. The controlled release formulation according to claim 24, wherein the carvedilol salt, solvate or anhydrous form thereof is an acid addition salt of carvedilol free base.
33. The controlled release formulation according to claim 32, wherein the acid addition salt of carvedilol free base is formed from a mineral acid or an organic acid.
34. The controlled release formulation according to claim 33, wherein the mineral acid is selected from hydrobromic acid, hydrochloric acid, phosphoric or sulphuric acid, and the organic acid is selected from methansulphuric acid, tartaric acid, maleic acid, acetic acid, citric acid, benzoic acid and the like.
35. The controlled release formulation according to claim 24, wherein the carvedilol salt, solvate or anhydrous form thereof is selected from the group consisting of carvedilol mandelate, carvedilol lactate, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, carvedilol mesylate, carvedilol phosphate, carvedilol citrate, carvedilol hydrogen bromide, carvedilol oxalate, carvedilol hydrogen chloride, carvedilol hydrogen bromide, carvedilol benzoate, and corresponding solvates thereof.
36. The controlled release formulation according to claim 35, wherein the carvedilol salt, solvate or anhydrous form thereof is carvedilol phosphate.
37. The controlled release formulation according to claim 35, wherein the carvedilol salt, solvate or anhydrous form is selected from the group consisting of carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dehydrate, carvedilol dihydrogen phosphate methanol solvate, carvedilol hydrobromide monohydrate, carvedilol hydrobromide dioxane solvate, carvedilol hydrobromide 1-pentanol solvate, carvedilol hydrobromide 2-methyl-1-propanol solvate, carvedilol hydrobromide trifluoroethanol solvate, carvedilol hydrobromide 2-propanol solvate, carvedilol hydrobromide n-propanol solvate #1, carvedilol hydrobromide n-propanol solvate #2, carvedilol hydrobromide anhydrous forms or anhydrous forms, carvedilol hydrobromide ethanol solvate, carvedilol hydrobromide dioxane solvate, carvedilol monocitrate monohydrate, carvedilol mandelate, carvedilol lactate, carvedilol hydrochloride, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, or corresponding anhydrous forms, solvates thereof.
38. The controlled release formulation according to claim 37, wherein the carvedilol salt, solvate or anhydrous form thereof is selected from the group consisting of carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dehydrate, carvedilol dihydrogen phosphate methanol solvate.
39. The controlled release formulation according to claim 38, wherein the carvedilol salt, solvate or anhydrous form thereof is carvedilol dihydrogen phosphate hemihydrate.
40. A controlled-release microparticle composition or formulation, which comprises:

a tri-component controlled-release microparticle composition or formulation product formed from:

[1] a first rapidly releasing microparticle population comprised of rapidly releasing microparticles;
wherein each rapidly releasing microparticle contains a layer comprised of carvedilol free base or a carvedilol, salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients applied to a cellulose sphere or a cellulose core; and [2] a first controlled release microparticle population comprised of first controlled release microparticless;
wherein each first controlled release microparticle contains a layer comprised of carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or pharmaceutically acceptable excipients applied to a cellulose sphere or a cellulose core;~
wherein each first controlled release microparticle is coated with at least one release controlling coating layer(s) formed from a film forming polymer and a plasticizing agent or other pharmaceutically acceptable materials to form each first controlled release microparticle;
and wherein each first controlled release granule triggers a release of the carvedilol free base, or the carvedilol salt, solvate, or anhydrous form thereof at a pH of about 5.5;
[3] a second controlled release microparticle population comprised of second controlled release microparticle granules;
wherein each second controlled release microparticle contains a layer comprised of carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer and pharmaceutically acceptable excipients applied to a cellulose sphere or a cellulose core;

wherein each second controlled release microparticle is coated with at least one release controlling coating layer(s) formed from a film forming polymer, or mixtures thereof and a plasticizing agent to form each second controlled release microparticle; and wherein each second controlled release granule triggers a release of the carvedilol free base, or the carvedilol salt, solvate, or anhydrous form thereof at a pH of about pH > 6.4; and wherein each rapidly releasing population, first controlled release population and second controlled release population further are admixed with pharmaceutically acceptable adjuvants, carriers or excipients to form the tri-component controlled-release microparticle-containing dosage form.
41. A controlled-release microparticle composition or formulation, comprises:

a tri-component controlled-release microparticle composition, formulation or dosage product formed from:

[1] a first rapidly releasing microparticle population comprised of microparticle rapidly releasing granules;

wherein each rapidly releasing microcapsule population is comprised of microparticle rapidly releasing granules each of which contain a layer comprised of carvedilol free base, or a carvedilol salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients applied to a cellulose sphere or core or other pharmaceutically acceptable core;and [2] a first controlled release microparticle population comprised of first controlled release microparticle granules;

wherein each first controlled release population is comprised of first controlled release microparticle granules each of which contain a layer comprised of carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients applied to a cellulose sphere or core or other pharmaceutically acceptable core;

wherein each first controlled release microparticle is coated with at least one release controlling coating layer(s) formed from a film forming polymer and a plasticizing agent to form each first controlled release microparticle; and wherein each first controlled release granule triggers a release of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof at a pH of about 5.5.

[3] a second controlled release microparticle population comprised of second controlled release microparticle granules;

wherein each second controlled release population is comprised of second controlled release microparticle granules each of which contain a layer comprised of carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or pharmaceutically acceptable excipients applied to a cellulose sphere or core or pharmaceutically acceptable core ;

wherein each second controlled release microparticle is coated with at least one release controlling coating layer(s) formed from a film forming polymer and a plasticizing agent to form each second controlled release microparticle; and wherein each second controlled release granule triggers a release of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof at a pH of about pH > 6.4; and wherein each rapidly releasing population, first controlled release population and second controlled release population are admixed with pharmaceutically acceptable adjuvants, carriers or excipients to form the tri-component controlled-release microparticle composition or formulation product.
42. A controlled-release microparticle composition, formulation or dosage form, which comprises:

a tri-component controlled-release microparticle composition or formulation product formed from:

[1] a first rapidly releasing microparticle population comprised of microparticle rapidly releasing granules;

wherein each microparticle rapidly releasing granule contains a layer comprised of a carvedilol phosphate salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients applied to a cellulose sphere or pharmaceutically acceptable core; and (2] a first controlled release microparticle population comprised of first controlled release microparticle granules;

wherein each first controlled release microparticle granulecontains a layer comprised of a carvedilol phosphate salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients applied to a cellulose sphere or pharmaceutically acceptable core;

wherein each first controlled release microparticle is coated with at least one release controlling coating layer(s) formed from a film forming polymer and a plasticizing agent to form each first controlled release microparticle; and wherein each first controlled release granule triggers a release of the carvedilol phosphate, salt, solvate, or anhydrous form thereof at a pH of about 5.5;

[3] a second controlled release microparticle population comprised of second controlled release microparticle granules;

wherein each second controlled release microparticle granule contains a layer comprised of a carvedilol phosphate salt, solvate, or anhydrous form thereof, at least one nitrogen containing polymer and a plasticizer or other pharmaceutically acceptable excipients applied to a cellulose sphere or pharmaceutically acceptable core;

wherein each second controlled release microparticle is coated with at least one release controlling coating layers) formed from a film forming polymer and a plasticizing agent to form each second controlled release microparticle; and wherein each second controlled release granule triggers a release of the carvedilol phosphate salt, solvate, or anhydrous form thereof at a pH of about pH > 6.4; and wherein each rapidly releasing population, first controlled release population and second controlled release population are admixed with pharmaceutically acceptable adjuvants, carriers or excipients to form the tri-component controlled-release microparticle composition, formulation or dosage form.
43. The controlled release formulation according to claim 42, wherein each rapidly releasing population, first controlled release population and second controlled release population are in a 1: 3: 4 active drug content ratio.
44. The controlled release formulation according to claim 42, wherein the carvedilol phosphate salt, solvate or anhydrous form is selected from the group consisting of carvedilol hydrogen phosphate, carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen phosphate dehydrate, carvedilol dihydrogen phosphate methanol solvate.
45. The controlled release formulation according to claim 43, wherein the carvedilol phosphate salt, solvate or anhydrous form is carvedilol dihydrogen phosphate hemihydrate.
46. The controlled release formulation according to claim 42, wherein:

each microparticle rapidly releasing granule contains a carvedilol phosphate salt, solvate, or anhydrous form thereof contained in a dosage amount of 1.25 mg to 10 mg; and each first controlled release microparticle granule contains a carvedilol phosphate salt, solvate, or anhydrous form thereof contained in a dosage amount of about 10 mg to about 80 mg.
47. The controlled release formulation according to claim 42, wherein a total dosage amount of the carvedilol phosphate salt, solvate, or anhydrous form thereof dosage amount contained in a sum of each first rapidly releasing microparticle granule, a first controlled release microparticle granule and a second controlled release microparticle granule is the sum of the total dosage amount between about 10 mg to about 80 mg.
48. The controlled release formulation according to claim 42, wherein each first controlled release microparticle granule and second controlled release microparticle granules further contain swelling agents selected from crosslinked polyvinylpyrrolidones, crosslinked carboxyalkylcelluloses, hydrophilic polymers of high molar mass, hydroxyalkylcelluloses, carboxyalkylcellulose, modified starch, starch, cellulose, sodium alginate, potassium polacriline, or corresponding blends thereof.
49. The controlled release formulation according to claim 48, wherein each first controlled release microparticle granule and second controlled release microparticle granules, wherein:

the crosslinked polyvinylpyrrolidones are selected from polyplasdone or crospovidone;

the crosslinked carboxyalkylcelluloses are selected from crosslinked carboxymethylcellulose or crosslinked sodium croscarmellose;

the hydrophilic polymers of high molar mass of greater than or equal to 100000 Dalton are selected from:

polyvinylpyrrolidone, polyalkylene oxides selected from polyethylene oxide or polypropylène oxide;

hydroxyalkylcelluloses selected from hydroxypropylcellulose or hydroxypropylmethylcellulose;

carboxyalkylcellulose selected from carboxymethylcellulose;

modified starch selected from sodium glycolate;

starch selected from corn , wheat, rice, or potato;

cellulose in a powder form or microcrystalline form;

sodium alginate;

potassium polacriline; and corresponding blends thereof.
50. The controlled release formulation according to claim 49, wherein the swelling agent is selected from:

the crosslinked polyvinylpyrrolidones selected from polyplasdone or crospovidone; or the crosslinked carboxyalkylcelluloses selected from crosslinked carboxymethylcellulose or crosslinked sodium croscarmellose.
51. The controlled release formulation according to claim 42, wherein the nitrogen-containing polymer in each first controlled release microparticle granule and second controlled release microparticle granule is a swelling agent.
52. The controlled release formulation according to claim 52, wherein the nitrogen containing polymers are selected from polyvinyl pyrrolidone (povidone or PVP), or cross-linked polyvinyl pyrrolidone (cross-linked povidone).
53. The controlled release formulation according to claim 42, wherein the nitrogen containing polymer in each first controlled release microparticle granule and in each second controlled release microparticle granule is a combination of polyvinyl pyrrolidone (povidone or PVP), or cross-linked polyvinyl pyrrolidone (cross-linked povidone).
54. The controlled release formulation according to claim 48, wherein in each of the first microparticle rapidly releasing granules, the first controlled release microparticle granules and the second controlled release microparticle granules, the plasticizer or the other pharmaceutically acceptable excipients selected from surface-active or lubricating agents are selected from castor oil, diethyl phthalate, triethyl citrate, salicylic acid, magnesium stearate, sodium oleate or polyoxyethylenated sorbitan laurate.
55. The controlled release formulation according to claim 42, wherein at least one release controlling layer is formed from at least one film forming polymer and a plasticizing agent in a ratio from about 60% (w/w) to about 40%
(w/w).
56. The controlled release formulation according to claim 42, wherein the film forming polymer in at least one release controlling coating layer(s) of each first controlled release microparticle is selected from a polymethylmethacrylate polymer selected from Eudragit L, Eudragit RL, Eudragit RS, other Eudragit NE polymers, Acrycoat S100, or Acrycoat L 100D.
57. The controlled release formulation according to claim 42, wherein the plasticizing agent in at least one release controlling coating layer(s) of each first controlled release microparticle is selected from a hydrogenated vegetable oil, propan 2-0l or propylene glycol, diethyl phthalate or other pharmaceutically acceptable materials.
58. A microparticle composition or formulation, which comprises:
a mixture of:
[a] rapidly releasing microparticles containing a carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof; and [b] at least two types of controlled-release microparticles containing carvedilol free base or a carvedilol salt, solvate, or anhydrous form thereof;
wherein the rapidly releasing microparticles contain a first dosage amount of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof different than each of the dosage amounts contained in at least two different types of delayed or controlled-release microparticles; and wherein the rapidly releasing microparticles exhibit different serial or sequential release for the first dosage amount of carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof than the dosage amounts contained in the at least two different types of controlled release microparticles.
59. The microparticle composition or formulation according to claim 56, wherein the different serial or sequential release of the rapidly releasing microparticles and at least two types of controlled release microparticles are defined by a mean plasma level representing a total carvedilol dosage amount as shown by a substantially biphasic profile;
wherein a total carvedilol dosage amount is the sum of the first and second dosage amounts;
wherein the rapidly releasing microparticles comprising the carvedilol free base or the carvedilol salt, solvate or anhydrous form thereof provide a peak plasma level at about 1 to 3 hours after dosing and each of the at least two types of delayed-controlled release microparticles release the carvedilol free base or the carvedilol salt, solvate or anhydrous form thereof provide a second peak plasma level between 5 to 10 hours after dosing.
60. The microparticle composition or formulation according to claim 56, wherein the serial or sequential release of the total carvedilol dosage amount from the rapidly releasing microparticles and at least two types of controlled release microparticles provide prolonged plasma levels as characterized by a substantially biphasic profile and residual drug plasma levels 24 hours after dosing comparable to a conventional carvedilol free base dosage dosed twice daily at 12 hour intervals for a total 24 hour period.
61. A controlled-release microparticle formulation for once-a-day administration, which comprises:
a microparticle mixture ratio formed from an rapidly releasing microparticle population, a first delayed release microparticle population;
and a second delayed release microparticle population;
wherein each of the microparticles in each population contain carvedilol free base, salt, solvate, or anhydrous form thereof in a different dosage amount adapted to provide controlled release of the different dosages contained in each microparticle populations to achieve comparable total plasma or total time concentrations (Area Under Curve) and plasma levels at C24 hours comparable to a conventional(rapidly releasing) carvedilol composition dosed twice daily at 12 hour intervals.;
wherein each of the first, second, and third dosage form has a different release profile, said microparticle product reaching a first peak plasma concentration level between about 1 hour to about 3 hours after dosing the controlled-release microparticle formulation and a second peak plasma concentration level between about 5 hours to about 10 hours after dosing the controlled-release microparticle formulation.
62. The controlled release microparticle formulation of claim 59, wherein the release profile is a substantially biphasic profile shown by:
first release microparticles exhibiting a release rate of the carvedilol free base or carvedilol salt, solvate, or anhydrous form thereof providing a first peak plasma concentration level between 1 to 3 hours after dosing the microparticle composition or formulation; and each of the at least two types of controlled release microparticles exhibiting a release rate of the carvedilol free base or the carvedilol salt, solvate, or anhydrous form thereof providing a second peak plasma concentration level between 5 to 10 hours after dosing the microparticle composition or formulation exhibiting a combined higher peak plasma concentration level than for the first release microparticles;
wherein the first peak plasma concentration level and the second peak plasma concentration level are in a ratio of about 0.5:1.0; and wherein a total of peak plasma concentration levels contributed by either the first release microparticles or each of the two types of delayed controlled release microparticles are substantially comparable to Cmax levels for an rapidly releasing carvedilol free base composition dosed twice daily at 12 hour intervals.
63. The controlled release microparticle formulation according to claim 60, wherein the the first peak plasma concentration level with a first T
max pulse occurs within 1-3 hours of ingestion and the second peak plasma concentration level with a second T maX pulse occurs within 5-10 hours after ingestion.
64. A controlled release microparticle dosage product, comprising:
a first immediate-release dosage form;
a second delayed release dosage form; and a third delayed release dosage form, wherein each of said first, second and third dosage forms comprise carvediloll free base or a carvedilol salt, solvate or anhydrous form thereof and a pharmaceutically acceptable carrier(s), said three dosage forms having different release profiles, said microparticle dosage product reaching a first peak plasma level from about 1 to about 3 hours and a second peak plasma level from about 5 hours to about 10 hours.
65. The controlled release microparticle dosage product of claim 62, wherein the first immediate-release dosage form; the second delayed release dosage form; and the third delayed release dosage form includes a total dosage of the carvedilol free base or the carvedilol salt, solvate or anhydrous form thereof that is effective for a twenty four hour period.
66. A method of treating cardiovascular diseases, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation according to claim 1.
67. The method of treating cardiovascular diseases of claim 64, wherein cardiovascular diseases are selected from the group consisting of hypertension, atherosclerosis, congestive heart failure and angina.
68. A method of treating hypertension, atherosclerosis, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation according to claim 21.
69. A method of treating hypertension, atherosclerosis, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation according to claim 22.
70. A method of treating hypertension, atherosclerosis, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation according to claim 23.
71. A method of treating hypertension, atherosclerosis, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation according to claim 39.
72. A method of treating hypertension, atherosclerosis, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation according to claim 40.
73. A method of treating hypertension, atherosclerosis, congestive heart failure or angina, which comprises administering to a subject in need thereof an effective amount of the controlled release formulation according to claim 41.
CA002547137A 2003-11-25 2004-11-24 Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods Abandoned CA2547137A1 (en)

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US8734850B2 (en) 2014-05-27
ES2662903T3 (en) 2018-04-10
EP1691789B1 (en) 2017-12-20
EP1691789A4 (en) 2012-08-08
USRE47084E1 (en) 2018-10-16
JP2012140440A (en) 2012-07-26
JP5072364B2 (en) 2012-11-14
WO2005051322A3 (en) 2006-04-20
WO2005051322A2 (en) 2005-06-09
US20050175695A1 (en) 2005-08-11
JP2007512375A (en) 2007-05-17

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